EGFR Degraders to Treat Cancer Metastasis to the Brain or CNS

Abstract

The invention provides for the treatment of mutant epidermal growth factor receptor (EGFR) mediated cancer that has metastasized to the brain or other area of the central nervous system with a compound that degrades a mutant form of EGFR via the ubiquitination of the EGFR protein and subsequent proteasomal degradation. The invention also provides advantageous drug combinations for the treatment of such cancer that include a compound herein that degrades a mutant form of EGFR in combination with a second anti-cancer agent.

We claim: 
     
         1 . A method of treating a brain or central nervous system metastasis of an EGFR mediated cancer in a human patient comprising administering an effective amount of a compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof to a human patent in need thereof, 
         wherein:
 B* is heteroaryl or aryl, each of which is optionally substituted with 1, 2, or 3 R 31  substituents; 
 y is 0 or 1; 
 R 31  is independently selected at each occurrence from the group consisting of F, Cl, Br, C 1-6 -alkyl, cyano, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, C 3-8 -cycloalkyl, and halo-C 3-8 -cycloalkyl and can be located on either ring when present on a bicycle; 
 R 32  is hydrogen, F, Cl, Br, C 1-6 -alkyl, C 3-8 -cycloalkyl, or halo-C 3-8 -cycloalkyl; and 
 R 33  is hydrogen, F, Cl, Br, C 1-6 -alkyl, C 3-8 -cycloalkyl, or halo-C 3-8 -cycloalkyl and can be located on the dihydropyrrole or imidazole ring. 
 
       
     
     
         2 . The method of  claim 1 , wherein B* is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 2 , wherein y is 1. 
     
     
         4 . The method of  claim 3 , wherein R 31  is selected from the group consisting of F, C 1-6 -alkyl, cyano, C 1-6 -alkoxy, and halo-C 1-6 -alkyl. 
     
     
         5 . The method of  claim 3 , wherein R 31  is F. 
     
     
         6 . The method of  claim 5 , wherein R 32  is hydrogen. 
     
     
         7 . The method of  claim 6 , wherein R 33  is hydrogen. 
     
     
         8 . The method of  claim 1 , wherein B* is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 8 , wherein R 31  is selected from the group consisting of F, C 1-6 -alkyl, cyano, C 1-6 -alkoxy, and halo-C 1-6 -alkyl. 
     
     
         10 . The method of  claim 9 , wherein R 32  is hydrogen. 
     
     
         11 . The method of  claim 10 , wherein R 33  is hydrogen. 
     
     
         12 . The method of  claim 1 , wherein the compound is of structure: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The method of  claim 1 , wherein the compound is of structure: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The method of  claim 1 , wherein the compound is of structure: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The method of  claim 1 , wherein the EGFR mediated cancer is a lung cancer. 
     
     
         16 . The method of  claim 15 , wherein the lung cancer is non-small cell lung cancer. 
     
     
         17 . The method of  claim 15 , wherein the lung cancer is small cell lung cancer. 
     
     
         18 . The method of  claim 1 , wherein the EGFR mediated cancer is adenocarcinoma. 
     
     
         19 . The method of  claim 1 , wherein the EGFR mediated cancer is selected from the group consisting of squamous cell lung cancer, large-cell undifferentiated carcinoma, neuroendocrine carcinoma, sarcomatoid carcinoma, adenosquamous carcinoma, oat-cell cancer, combined small cell carcinoma, lung carcinoid tumor, central carcinoid, peripheral carcinoid, salivary gland-type lung carcinoma, mesothelioma, mediastinal tumor, colorectal cancer, rectal cancer, head and neck cancer, esophageal cancer, pancreatic cancer, thyroid cancer, ovarian cancer, uterine cancer, cervical cancer, kidney cancer, liver cancer, bladder cancer, and melanoma. 
     
     
         20 . The method of  claim 1 , wherein the EGFR mediated cancer is breast cancer. 
     
     
         21 . The method of  claim 20 , wherein the breast cancer is HER-2 positive breast cancer. 
     
     
         22 . The method of  claim 20 , wherein the breast cancer is estrogen receptor positive breast cancer. 
     
     
         23 . The method of  claim 20 , wherein the breast cancer is progesterone receptor positive breast cancer. 
     
     
         24 . The method of  claim 20 , wherein the breast cancer is triple negative breast cancer. 
     
     
         25 . The method of  claim 1 , wherein the EGFR mediated cancer is relapsed and/or refractory. 
     
     
         26 . The method of  claim 1 , wherein the compound is administered orally. 
     
     
         27 . The method of  claim 26 , wherein the compound is administered orally by a tablet administration. 
     
     
         28 . The method of  claim 26 , wherein the compound is administered orally by a capsule administration. 
     
     
         29 . The method of  claim 1 , wherein the compound is administered parenterally. 
     
     
         30 . The method of  claim 29 , wherein the compound is administered intravenously.